Migraine is a chronic, episodic, and debilitating primary headache syndrome that affects about 15 to 20% of the world population. Arunagiri et al., Curr. Opin. Opthalmol 14:344-352 (2003). Migraine has two main types. One type, migraine without aura (previously known as common migraine), affects about 15% of the population. In migraine without aura, the headache is unilateral, pulsating, and moderate to severe in intensity, and may last a few hours to 3 days. The headache may also be associated with nausea, vomiting, photophobia, phonophobia, and other symptoms. The second type, migraine with aura (previously known as classic migraine), affects about 8% of the population. In migraine with aura, one or more auras, such as visual, somatosensory, and motor symptoms, develop prior to the development of a migraine attack. Migraine without aura and migraine with aura co-occur in 13% of migraineurs.
The two prevailing views of migraine pathophysiology are the neuronal and trigeminovascular theories. In the neuronal hypothesis, cortical spreading depression (CSD), a slowing of electroencephalographic activity that propagates across the cortex at 3-5 mm/min, has been recorded during migraine aura. The trigeminovascular hypothesis asserts that an altered modulation of the perivascular nerves of the intracranial vessels sensitizes the nociceptive perivascular fibers' projection to the trigeminal caudate nucleus, which propagates the headache. The current model of migraine is an integration of these two theories linking the intrinsic brain activity of CSD with trigeminal meningeal afferents. In addition, Moskowitz and colleagues present logic to explain the loss/gain of functions found in two different familial hemiplegic migraine genes with the migraine phenotype. However, the basis for hypersensitivity features of migraine—pain, photophobia, phonophobia, osmophobia, nausea, vomiting, and confusion—remains unexplained.
Calcium channel, sodium transporter, and sodium channel gene mutations have been found in familial hemiplegic migraine. For example, mutations in the slow calcium channel gene (CACNA1A), the Na+, K+-ATPase transporter gene (ATP1A2), or the voltage-gated sodium channel gene (SCN1A) underlie cases of the rare familial hemiplegic migraine. Pharmaceuticals with calcium or sodium channel blocking activities have also been shown to be useful in migraine prophylaxis. Although these studies suggest that ion transport may be implicated in migraine pathogenesis, a link between sodium homeostasis and migraine has never been established.
Campbell and colleagues reported in 1951 that blood sodium levels in migraine are increased, and were accompanied by a decrease in protein that they attributed to overhydration. Campbell et al., Br. Med. J. 1951, 4745:1424-1429. The reference used a gavimetric method based on pyroantimonate, which has now been abandoned as being indirect. The reference also did not address variations of sodium levels from circadian rhythm fluctuation, a phenomenon that had not been identified at the time of the study. Meanwhile, Jowett reported that sodium and potassium levels were within normal ranges when measured by flame photometry in cerebrospinal fluids from 20 patients during migraine attack. Jowett, Brain, 1967, 90(4):785-94. That study did not compare the levels of well with sick migraineurs, and its controls were ill-defined. Brainard reported salt loading as a trigger of migraine. Brainard J. B., Minn. Med. 1976, 59(4):232-233. He correlated this phenomenon with increased plasma angiotensin and aldosterone levels rather than sodium levels. None of these references provide a correlation between sodium level in the brain extracellular fluid/cerebrospinal fluid and migraine.
Use of sodium pump inhibitors to treat various diseases has been disclosed in U.S. Pat. No. 5,872,103, U.S. Pat. Pub. No. 2003/0229029, and WO05/102371.
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